European Journal of Clinical Pharmacology

, Volume 62, Issue 8, pp 589–595

Iloprost for prevention of contrast-mediated nephropathy in high-risk patients undergoing a coronary procedure. Results of a randomized pilot study

Authors

    • Onassis Heart Centre
  • E. Adreanides
    • Onassis Heart Centre
  • G. Giamouzis
    • Onassis Heart Centre
  • S. Karagiannis
    • Onassis Heart Centre
  • A. Gouziouta
    • Onassis Heart Centre
  • A. Manginas
    • Onassis Heart Centre
  • V. Voudris
    • Onassis Heart Centre
  • G. Pavlides
    • Onassis Heart Centre
  • D. V. Cokkinos
    • Onassis Heart Centre
Clinical Trials

DOI: 10.1007/s00228-006-0150-y

Cite this article as:
Spargias, K., Adreanides, E., Giamouzis, G. et al. Eur J Clin Pharmacol (2006) 62: 589. doi:10.1007/s00228-006-0150-y

Abstract

Objective

The prevention of contrast-mediated nephropathy (CMN), which accounts for considerable morbidity and mortality, remains a vexing problem. Contrast induced renal vasoconstriction is believed to play a pivotal role in the CMN mechanism. The aim of this pilot study was to examine the safety and efficacy of two doses of the prostacyclin analogue iloprost in preventing CMN in high-risk patients undergoing a coronary procedure.

Methods

Forty-five patients undergoing coronary angiography and/or intervention who had a serum creatinine concentration ≥1.4 mg/dL were randomized to receive iloprost at 1 or 2 ng/kg/min or placebo, beginning 30–90 minutes before and terminating 4 hours after the procedure. CMN was defined by an absolute increase of serum creatinine ≥0.5 mg/dL or a relative increase of ≥25% measured 2 to 5 days after the procedure. Study drug infusion was discontinued in 2 patients in the low-dose iloprost group due to flush/nausea and in 5 patients in the high-dose group due to severe hypotension.

Results

The mean creatinine concentration change in the placebo group (0.02 mg/dL) was unfavorable compared to that in the low-dose iloprost group (−0.11 mg/dL; p=0.08) and high-dose iloprost group (−0.23 mg/dL; p=0.048). The difference between the absolute changes in creatinine clearance was favorable compared to placebo for both the low (mean difference 6.1 mL/min, 95%CI −0.5 to 12.8 mL/min, p=0.07) and the high-dose iloprost group (11.8 mL/min, 95%CI 4.7 to 18.8 mL/min, p=0.002). Three cases of CMN were recorded; all in the placebo group (p=0.032).

Conclusions

The results of this pilot study suggest that prophylactic administration of iloprost may effectively prevent CMN, but higher dosages are connected with substantial tolerability issues.

Keywords

Contrast nephropathyCoronary angiogrphyIloprostProstacyclinProstaglandins

Introduction

The acute decline in renal function caused by the intravascular administration of iodinated contrast agents is generally mild and transient, but some patients may experience a more prolonged decrease and, in rare cases, require temporary or permanent renal replacement therapy. The most commonly used definition of contrast mediated nephropathy (CMN) is an absolute increase in serum creatinine concentration of at least 0.5 mg/dl or a relative increase of at least 25% from the baseline value [1]. A plethora of clinical data has shown a strong and consistent relationship between the development of this complication and unfavorable morbidity and mortality outcomes and prolonged hospital stays [27]. Even mild increases of serum creatinine (referred to by some as “creatinopathy”) may have severe adverse clinical consequences.

Unfortunately, an effective CMN prevention strategy has been an elusive goal. With the exception of intravenous hydration, attempts to prevent CMN by the prophylactic use of various agents have generally met with failure [8]. What continues to fuel the search for an effective prevention strategy is the increasing number of patients suffering CMN as a consequence of the ever increasing demand for procedures involving intravascular contrast medium injections.

Ischemic damage caused by the prolonged renal vasoconstrictive effects of contrast media is thought to play a pivotal role in the CMN mechanism. Adequate medullary blood flow is normally maintained by the interplay of vasodilator and vasoconstrictor influences, mediated by local nitric oxide, prostaglandin, adenosine, and endothelin systems within the medulla [9].

Prostaglandins (PG) E and I2 of the arachidonic acid cascade are the most important mediators of renal effects [10]. Animal experiments have shown that administration of contrast medium results in increased release of PGE’s but decreased release of PGI2 from the kidney [11]. To date, the only prostaglandin analogue investigated in humans with regards to CMN prevention is PGE1 (Alprostadil). In a small pilot study aimed at evaluating the preventative effects of three doses of Alprostadil compared to placebo, the increase in mean serum creatinine concentration at 48 h was significantly smaller for only the intermediate dose (20 ng/kg/min). Reduced increases in serum creatinine concentration compared to placebo were also noted for the lowest and highest doses (10 and 40 ng/kg/min) but these differences were not significant [12].

Iloprost, a stable prostacyclin (PGI2) analogue, has been shown to protect animal kidneys against ischemic and toxic insults and to significantly attenuate the effects of contrast media in the renal cortex of rats, as assessed by near-infrared reflection spectroscopy [13, 14]. Another synthetic analogue of prostacyclin, beraprost, has also been shown to protect against direct tubular damage and apoptosis induced by contrast media [15, 16]. These findings suggest that attenuation of the renal vasodilatory influence of PGI2 may be a critical factor underlying the development of CMN.

The present single-centre, randomized, double-blind, placebo-controlled pilot study was undertaken to further evaluate the possible preventative effects of iloprost on the development of CMN. Specifically, the present study was performed to preliminarily evaluate the potential nephroprotective efficacy and safety of two different doses of iloprost in selected patients undergoing a coronary procedure and considered to be at risk of developing CMN.

Materials and methods

Patients

Patients undergoing clinically driven, non-emergent coronary angiography or intervention in our institution were eligible for inclusion if their serum creatinine concentration was ≥1.4 mg/dl (124 μmol/l) and/or their creatinine clearance was <60 ml/min on their most recent sample drawn within 1 month of the planned procedure. The definition of a non-emergent coronary procedure was: (1) at least 2 h between acute hospital admission and admission to the catheterization laboratory, and (2) not intending to perform primary percutanous intervention for acute myocardial infarction.

Patients were excluded for any of the following reasons: circulatory shock, systolic blood pressure <95 mm Hg, known acute renal failure, end-stage renal disease requiring dialysis, intravascular administration of a contrast medium within the previous 10 days, anticipated re-administration of contrast medium within the following 6 days, inability to administer intravenous hydration at least 4 h before the procedure or study medication at least 30 min before the procedure, primary intervention for acute infarction with ST elevation, and a procedure performed within 2 h of acute hospital admission. The institutional research ethics committee and the National Drugs Administration approved the study protocol, and all patients gave written, informed consent before inclusion.

Study protocol

Forty-five patients were randomly assigned in a 1:1:1 fashion to receive intravenous iloprost at a dose of 1 or 2 ng/kg/min or placebo (saline). Randomization was performed locally in blocks of nine by means of sealed boxes. A Research Fellow not involved in the procedure was designated for preparation of the study drugs and for the random assignment of treatment. Study drug infusion was commenced 30–90 min before contrast administration and continued for 4 h after its end. Infusion of the study drug was initiated at half of the target dose and was uptitrated to the final dose in the catheterization laboratory after arterial sheath insertion and invasive blood pressure determination. The vital signs were monitored during study drug infusion.

Intravenous hydration with 1.5 ml/kg/h normal saline was started in all patients at least 4 hours before contrast exposure and continued for at least 12 h after the procedure. All patients were encouraged to drink if they were thirsty. The choice of the type of contrast medium was left to the interventional cardiologist performing the procedure, but use of a non-ionic iso- or low-osmolar contrast medium was encouraged.

Determinations of serum creatinine concentration were performed on blood samples drawn at the time of randomization (baseline), on blood samples drawn on the morning and evening of the day following the procedure, and on blood samples drawn at 2–5 days after the procedure (follow-up; a single measurement). All measurements were performed in a single, hospital-based laboratory with consistent methodology. Creatinine clearance at baseline and 2- 5-day follow-up was calculated by applying the Cockcroft-Gault formula, with adjustment for female patients [17].

Monitoring for adverse events was performed from the start of study drug infusion until the end of the follow-up period. Among all the adverse events recorded the following adverse safety outcomes were pre-specified: severe hypotension events requiring study drug discontinuation (systolic blood pressure <80 mm Hg), hypotension events requiring study drug non-uptitration or downtitration (systolic blood pressure <90 mm Hg for any reason, or an absolute drop from baseline of >40 mm Hg), bleeding complications.

Outcomes

This pilot study intended to attain information about the effectiveness of iloprost in CMN prevention, its possible dependency on dosage and to evaluate the safety of its administration in the examined patient population. Changes in serum creatinine concentration were used as the primary variable for verifying the effectiveness of dosage. Furthermore, variables attained on the basis of creatinine clearance estimations were used.

CMN was defined as an absolute increase of serum creatinine concentration of at least 0.5 mg/dl or a relative rise of at least 25% from baseline on the follow-up blood sample drawn at 2–5 days after the procedure.

Statistical methods

Explorative statistical methods were used to compare the different patient groups. Data are reported as mean±standard deviation (SD) for continuous variables and as percentages for discrete variables. Assuming a SD of 0.4 mg/dl in the mean follow-up serum creatinine concentration, we found that a sample size of approximately 15 patients per group would be required to detect a 0.2 mg/dl absolute difference between the study groups, with 80% power at the conventional 2-sided significance level of 5%.

Continuous variables were analyzed by the two-sample independent or paired t-test or one-way ANOVA, as appropriate. Discrete categorical variables were evaluated by the χ2 or Fisher exact test. The prespecified analysis was performed on an intention-to-treat basis in those patients in whom all protocol-specified serum creatinine measurements were obtained.

Differences in the progression of serum creatinine concentrations among the study groups were also explored by using the general linear model for repeated measurements.

All tests were 2-sided, and a significance level of 5% was used. Statistical analyses were performed with SPSS software (version 11.0.1, SPSS).

Results

Of the 45 patients randomized, 44 completed the study (Fig. 1). One patient failed to return for the follow-up creatinine measurement. None of the 45 patients developed acute renal failure requiring dialysis. The baseline clinical, biochemical, and procedural characteristics for the remaining 44 patients are shown in Table 1. The mean times of follow-up serum creatinine concentration measurement were similar in the study groups: placebo 3.3±1.2 days, iloprost 1 ng/kg/min 3.1±1.3 days, iloprost 2 ng/kg/min 2.9±1.1 days (p=0.65).
https://static-content.springer.com/image/art%3A10.1007%2Fs00228-006-0150-y/MediaObjects/228_2006_150_Fig1_HTML.gif
Fig. 1

Flow chart of study progress

Table 1

Clinical and procedural characteristics of study patients

 

Iloprost

Iloprost

Placebo

1ng/kg/min

2ng/kg/min

n=15

n=15

n=14

Age, years

73±7

69±9

72±9

Gender (M/F), n

15/0

13/2

12/2

BMI, kg/m2

27±3

28±4

27±3

LVEF

46±9

49±12

53±8

Contrast agent volume, ml

217±118

245±191

219±77

Contrast agent type (iso/low-osmolar), n

9/6

10/5

11/3

Total hydration given IV, ml

2,423±658

2,367±721

2,151±406

Type of procedure (diagnostic/intervention), n

8/7

8/7

7/7

Diabetes mellitus, n

7

8

7

Clinical heart failure, n

5

4

3

Systemic hypertensiona, n

13

15

12

Smoking, n

5

1

2

Diuretics, n

6

2

5

ACEI or ATRA, n

10

11

10

Statin, n

13

13

9

Body mass index (BMI) was calculated as the weight divided by the square of the height in meters. LVEF indicates left ventricular ejection fraction; ACEI, angiotensin-converting-enzyme inhibitor; and ATRA, angiotensin receptor antagonist

aRequiring pharmaceutical treatment. P=NS for all comparisons

Clinical events alluding to the safety profile of iloprost as a potential CMN preventative treatment are shown in Table 2. Iloprost infusion had to be discontinued in 5 (33%) patients randomized to the high dose group due to severe hypotension. This was not a problem in the low dose group; in this group 2 (13%) patients were discontinued due to other reasons (flush or nausea). Both these side effects reversed rapidly following treatment discontinuation, and there was no further clinical sequel. Blood loss related problems in the active treatment arms did not exceed those observed in the placebo arm.
Table 2

Safety profile of iloprost treatment

 

Iloprost

Iloprost

Placebo

1 ng/kg/min

2ng/kg/min

n=15

n=15

n=15

Discontinuation*

2

5

0

Downtitration

1

2

0

Discontinuation or downtitration**

2

6

0

Reason of discontinuation

 Systolic BP<80 mm Hg***

0

5

0

 Flush /nausea

2

0

0

Ht drop >5%

0

2

2

Transfused

0

1

2

CABG

0

0

1

Death/Q-w-AMI

0

0

0

Systolic BP change (mm Hg)****

−7±8

−8±14

2±11

Diastolic BP change (mm Hg)

0±11

−1±12

0±11

HR change (beats/minute)

8±6

7±7

10±3

*P=0.047, **P=0.012, ***P=0.004, ****P=0.07

BP, blood pressure; Ht, heamatocrit; CABG, coronary artery bypass grafting; AMI, acute myocardial infarction; HR, heart rate

The mean serum creatinine concentration remained relatively stable in the placebo group (Table 3) but decreased significantly in the high dose iloprost group (from 1.59±0.38 mg/dl to 1.36±0.36 mg/dl; p=0.013) and in all iloprost treated patients combined (from 1.65±0.54 mg/dl to 1.48±0.48 mg/dl; p=0.002). A trend for decrease in serum creatinine concentration was also noted in the low dose iloprost group (from 1.71±0.70 mg/dl to 1.60±0.57 mg/dl; p=0.083). Similar findings were observed in the changes of creatinine clearance: whereas a decrease in the rate of creatinine clearance was noted in the placebo group, a significant increase in the rate of clearance was noted in the high dose iloprost group.
Table 3

Baseline and follow-up serum urea, creatinine concentrations and creatinine clearance; absolute changes from baseline after administration of contrast agent; and incidence of CMN in the study groups

 

Iloprost

Iloprost

Placebo

P value

1ng/kg/min

2ng/kg/min

Serum urea concentrations, mg/dl

 

Baseline

73.1±24.7

58.6±18.0

60.9±12.9

0.115

Follow-up

69.9±28.2

46.9±15.7

52.1±14.5

0.012

P-value

0.153

0.012

0.009

 

Serum creatinine concentrations, mg/dl

Baseline

1.71±0.70

1.59±0.38

1.66±0.64

0.832

Follow-up

1.60±0.57

1.36±0.36a

1.68±0.51a

0.185

   

0.08a

P-value

0.083

0.013

0.839

 

Absolute change in creatinine concentration

−0.11±0.23b

−0.23±0.31c

0.02±0.44bc

0.139

   

0.08b

   

0.048c

Creatinine clearance, mL/min

    

Baseline

47.8±18.4

54.3±19.7

51.1±19.2

0.642

Follow-up

50.8±20.3

62.9±21.5d

48.0±16.5d

0.100

   

0.048d

Absolute change in creatinine clearance

3.0±8.2e

8.7±9.9f

−3.1±9.3ef

0.004

   

0.072e

   

0.001f

CMN, n

0

0

3

0.032

One-way ANOVA was used for the comparisons among the study groups and paired t-test for the comparisons within study groups. Fisher exact test was used for CMN comparison among the groups. Letters in cells indicate the comparisons used to produce the P-values marked with the same letters in the final column

The creatinine clearance for all iloprost treated patients combined increased from 51.0±19.1 ml/min to 56.9±21.5 ml/min (p=0.001). The difference between the absolute changes in creatinine clearance was favorable compared to placebo for both the low (mean difference 6.1 ml/min, 95% confidence interval [CI] −0.5 to 12.8 ml/min, p=0.07) and the high dose iloprost group (11.8 mL/min, 95% CI 4.7 to 18.8 ml/min, p=0.002), and for all iloprost treated patients combined (9.0 ml/min, 95% CI 2.8 to 15.1 ml/min, p=0.004). Figure 2 illustrates the progression of the average creatinine concentrations among the study groups at the pre-specified time points.
https://static-content.springer.com/image/art%3A10.1007%2Fs00228-006-0150-y/MediaObjects/228_2006_150_Fig2_HTML.gif
Fig. 2

Average serum creatinine concentrations in the study groups. GLM p=0.112 among study groups, p=0.132 between placebo and all iloprost patients

Three cases of CMN were recorded; in each case the patient was randomized to the placebo group. Based on the Fisher exact test the occurrence of CMN was significantly lower in the iloprost treatment groups than in the placebo group (p=0.032).

Discussion

This pilot study demonstrates that the PGI2 analogue iloprost at a dose of 1 ng/kg/min is safe and well-tolerated for peri-procedural administration to patients undergoing a coronary procedure who are at high risk for developing CMN. In contrast, the higher dose of 2 ng/kg/min iloprost was not well tolerated, since one-third of the patients receiving it developed serious hypotension necessitating discontinuation of the drug.

Although this pilot study was not designed specifically to explore the efficacy of iloprost for CMN prevention, the results are promising in that the renal function parameters following contrast exposure were more favorable in the active treatment groups than in the placebo group. The observed incidence of CMN in the placebo group (3/15; 20%) is in accordance with that noted previously in numerous studies [18]. Conversely, the incidence of CMN in the iloprost treated patients was zero. Although this finding was significant (p=0.032), the result is too preliminary to draw any firm conclusions and should be viewed solely as strengthening the promise of this new preventive treatment.

Significant hypotension in the process of obtaining arterial access for performing cardiac catheterization is not an unusual event and is usually attributed to vasovagal reactions. However, since hypotension is also the principal, dose-dependent side effect of iloprost, and no such event was noted in our placebo group, we regarded all hypotension events in the present study as being directly related to iloprost treatment. Severe hypotension due to iloprost is rapidly reversible because of its very short (12 min) half-life, and it normally responds well to the usual sustaining measures [19]. Nevertheless, the hypotension events experienced by five patients who received an iloprost dose of 2 ng/kg/min was considered severe enough to warrant study drug discontinuation. Conversely, no patient who received an iloprost dose of 1 ng/kg/min experienced hypotension considered severe enough to require study drug discontinuation. The safety profile of the iloprost 1 ng/kg/min dose was comparable to that of placebo, with the exception of minor side effects (i.e. facial flush and nausea). All our patients who experienced severe hypotension during the study responded within minutes from discontinuation of the study drug and to the intravenous administration of saline.

Another area of concern with regards to safety was the possibility of bleeding side effects at the arterial access site due to the platelet inhibition properties of iloprost [20]. However, the results of this pilot study are reassuring in that no patient in the low dose group experienced significant blood loss or required blood transfusion. Indeed, this dose of iloprost causes minor (<50%) inhibition of adenosine diphosphate-induced platelet aggregation and has no effect on the intrinsic clotting system, plasma coagulation tests and template bleeding time. The antiplatelet effect of iloprost is short lived and rapidly eliminated [20, 21].

Despite the small size of this study, the preliminary findings suggest a dose-related effect of iloprost on CMN prevention. However, in view of the safety profiles of the two evaluated doses of iloprost, the dose selected for further large scale study is the low 1 ng/kg/min dose of iloprost.

It is currently believed that disturbances in renal hemodynamics and direct tubular epithelial cell toxicity by contrast media are the primary factors responsible for CMN [16]. A number of compounds that improve renal blood flow have been clinically tested for prevention of CMN, but none has proven effective [8]. On the other hand, several recent clinical trials have shown that antioxidant agents such as N-acetylcysteine and ascorbic acid are partially effective in CMN prevention, suggesting that oxidative stress may play a role in its development [8, 22]. However, both the above antioxidant agents are established protectors of endogenously produced nitric oxide (NO) and modulation of renal hemodynamics by means of the NO system may play a role [23].

Contrast media cause a short-lived, transient increase of renal blood flow followed by a prolonged decrease [24]. Contrast medium-induced renal vasoconstriction has been documented repeatedly and is the basis for the hypothesis that renal ischemia is a major factor in the pathogenesis of CMN [24]. The renal medulla normally has an extremely low oxygen tension as a result of the countercurrent exchange of oxygen and the high transport activity of the medullary thin ascending limb (mTAL). The low oxygen tension in this area of the kidney makes it uniquely susceptible to ischemic injury from factors that may diminish blood flow or increase oxygen utilization. Renal vasoconstriction and hyperosmolality that increase transport work requirement in the mTAL, a process requiring oxygen utilization, are the mechanisms by which contrast media worsen medullary hypoxia and induce renal injury. In addition, they cause blood cell aggregation, which can further impair oxygen delivery [25].

Administration of contrast media in dogs has been shown to cause: (1) an initial brief increase followed by a sustained 20% decrease in renal blood flow and creatinine clearance; (2) no significant changes in angiotensin II and rennin levels; and (3) a significant decline in the renal secretory rate of 6-keto-PGF1a, a PGI2 metabolite. These observations suggest that suppression of prostacyclin, rather than activation of the rennin-angiotensin system, is a principal cause of CMN [26]. In this regard, contrast media have been shown to increase release of PGEs but to decrease release of PGI2 from the kidney [11].

In vitro and in vivo studies in rats have shown that prostaglandins (PGE1, PGE2 and PGI2) protect the kidneys against ischemic and toxic injury by means of a cellular effect [13]. Co-administration of iloprost significantly attenuated the effects of contrast media in the renal cortex of rats, as assessed by near-infrared reflection spectroscopy [14]. Iloprost preserves rabbit kidney function against anoxia and attenuates ischemic acute renal failure in rats after clamping of left renal artery [27, 28]. Indomethacin, a prostanoid inhibitor, has been shown to reduce renal outer medulla blood flow following contrast medium administration and to cause radiocontrast toxicity in rats [29]. Although the protective effect of prostacyclin is considered to be due primarily to the vasodilatory action, a direct protective action on renal epithelial cells has also been shown in an in vitro model of hypoxia/reoxygenation-induced injury in cultured rat proximal renal tubular cells [13].

Additionally, PGI2 has been shown to mitigate the progression rate of renal dysfunction in patients with chronic renal insufficiency [30]. Moreover, low-dose prostacyclin (2 ng/kg/min) started immediately before cardiac surgery and continued for a maximum of 48 h has been shown to preserve renal function in high risk patients with impaired left ventricular fraction undergoing surgical revascularization [31].

It is known that the prostacyclin receptor is coupled to the stimulatory G protein (Gs) to enhance cAMP production [32] and it distributes to the glomerular cells, endothelial cells, distal tubules, and collecting ducts in human kidneys [33, 34]. It has been shown that ioversol-induced apoptotic injury in a porcine renal tubular cell line (LLC-PK1 cells) is attenuated by dibutyryl cyclic AMP (DBcAMP). The protective effect of DBcAMP is reversed by H89, an inhibitor of protein kinase A, suggesting an involvement of protein kinase A [15]. In addition, a recent study has shown that beraprost, a synthetic prostacyclin analogue, at concentrations ranging from 10 nM to 1000 nM attenuates the ioversol-induced decrease in the viability of LLC-PK1 cells in a concentration-dependent manner. In this study, the protective effect of beraprost was dependent on the elevation of cellular cyclic AMP content and activation of protein kinase A [16, 35].

Despite the excellent theoretical and experimental background suggesting a possible nephroprotective of PGI2, our pilot study is the first to report on the safety and effectiveness of a PGI2 analogue on CMN prevention in humans. This novel and promising approach is currently being further evaluated in a larger scale efficacy trial, which we expect to conclude within, 2006. Ito et al have also announced a clinical study to evaluate the effect of the orally administered prostacyclin analogue beraprost for CMN prevention in high-risk patients undergoing coronary angiography. This study, like ours, is currently ongoing. Taken together, these two studies should clarify whether prostacyclin analogues offer a breakthrough effective strategy for CMN prevention or merely represent one more failed approach on the long list of the failed CMN preventive measures.

Copyright information

© Springer-Verlag 2006